The long-term goal of this research is to develop orally active insulin mimetic drugs based on novel paradigms for the development of small molecule ligands for growth factor receptors. This goal will be accomplished by synthesis of natural product libraries using combinatorial chemistry and their screening against receptor tyrosine kinases, It will be aided by the identification of cytoplasmic proteins that bind to the novel insulin mimetic natural product demethylasterriquinone B1 (DAQ B1), and by direct examination of the interactions of DAQ B 1 with the insulin receptor cytoplasmic domain. The ultimate outcome of this research would be elimination of the need for insulin injections. This project will utilize the following methods: organic synthesis, medicinal and combinatorial chemistry, phage display cloning, and protein chemistry. Assays of the products will include in vitro and in cyto insulin receptor activation, and study of their cytotoxic and cellular transport properties. This research will be significant because substances that can elicit the same biological response as insulin but that are not proteins, and therefore may be orally active, would be of significant value in diabetes management. They would eliminate the need for hypodermic syringes/needles, obviating concerns about contamination and increasing the convenience of administration, with a likely enhancement in patient compliance. They would therefore increase the reliability of diabetes management, particularly for children.